A new study has shed light on a long-standing mystery in heart disease research: how mutations in the same gene can lead to two very different and dangerous heart conditions.
Scientists have discovered that small changes in one protein can cause the heart to either contract too strongly or not strongly enough—leading to hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), respectively.
These findings, published in the Journal of Clinical Investigation, could lead to better, more targeted treatments for people living with these life-threatening heart diseases.
HCM and DCM are among the most common inherited heart diseases. Both can cause serious problems like heart failure and sudden death, even in young, otherwise healthy people.
In HCM, the heart muscle becomes thickened, especially in the wall of the left ventricle, making it harder for the heart to pump blood. DCM is the opposite—the heart muscle becomes stretched and thin, weakening its ability to contract and pump blood effectively.
Despite their opposite effects on the heart, both conditions can be caused by changes in the same gene—specifically, a gene that produces a protein called tropomyosin, which plays a key role in how heart muscle contracts.
To understand how this happens, Professor Stuart Campbell and his research team at Johns Hopkins University used cutting-edge lab techniques to study two nearly identical mutations in the tropomyosin gene—one that causes HCM and one that causes DCM. They inserted each mutation into human stem cells and then turned those cells into heart muscle tissue in the lab.
The results were striking. The mutation linked to HCM caused hypercontractility—meaning the heart muscle was contracting too forcefully. This overactive muscle behavior matches what is seen in people with HCM, whose hearts become thick and stiff.
In contrast, the DCM-linked mutation caused hypocontractility, meaning the heart tissue wasn’t contracting enough—similar to what happens in DCM, where the heart becomes weak and enlarged.
The researchers also used computer models to dig deeper into the molecular behavior behind these mutations. They found that even though the mutations were close together—only eight amino acids apart in the protein—they disrupted heart muscle function in completely opposite ways.
To see if they could fix the problem, the scientists tested two drugs. For the overactive HCM tissue, they used mavacamten, a drug known to reduce muscle contraction. After just a few days of treatment, the tissue returned to normal levels of contraction.
For the weakly contracting DCM tissue, they used danicamtiv, a drug that boosts heart muscle strength. It too worked, restoring the heart tissue’s ability to contract properly.
These discoveries not only help explain why two diseases that look so different can come from changes in the same gene, but also offer hope for better treatment options. By understanding exactly how these mutations affect heart muscle function, doctors may eventually be able to match patients with the most effective drugs based on their specific genetic mutation.
“We wanted to show clearly how a small change in one protein can push the heart in totally different directions—toward either too much contraction or not enough,” Campbell explained. “By walking through every step from gene to disease, we’re hoping to make treatment more precise and effective for patients.”
This study is a powerful example of how detailed lab work can lead to real-world improvements in health care. Using engineered human heart tissue, the researchers were able to observe how individual genetic mutations affect heart function at a cellular level. This approach allowed them to precisely link each mutation with its corresponding disease behavior.
What’s particularly impressive is how the team not only identified the problem but also tested potential solutions. The fact that two existing drugs—mavacamten and danicamtiv—were effective in correcting the lab-grown heart tissue is highly promising.
It shows that with a better understanding of the root cause of these diseases, treatments can be customized for each patient, paving the way for more targeted and effective care.
This research also highlights the value of using lab-grown human tissue and computer models to study diseases. These methods offer a safe and highly controlled environment to explore questions that would be difficult or impossible to answer directly in human patients.
In the future, this kind of research could help doctors predict which patients are likely to benefit from specific drugs, reducing the trial-and-error approach that is often part of treating heart disease today. It’s a step toward personalized medicine—where treatments are based on each patient’s unique biology, rather than a one-size-fits-all solution.
If you care about heart disease, please read studies about a big cause of heart failure, and common blood test could advance heart failure treatment.
For more information about heart health, please see recent studies about a new way to repair human heart, and results showing drinking coffee may help reduce heart failure risk.
The research findings can be found in the Journal of Clinical Investigation.
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